This application addresses broad Challenge Area (01) Behavior, Behavioral Change and Prevention and specific Challenge Topic, 01-DA-110: Identify and/or evaluate dietary supplements that could be used in treating substance use disorders. Among US adults, 12.8% report nicotine dependence, and nicotine dependence is highly associated with a variety of DSM-IV Axis I and II disorders. Pathological gambling (PG), a serious public health problem with detrimental effects on individuals and families, and with an estimated yearly cost to society of 5 billion dollars due to lost jobs, debt, bankruptcy, and incarcerations, is associated with elevated proportions of nicotine dependence (41% - 55%), and tobacco smoking in clinical samples of pathological gamblers has been associated with increased gambling severity and more frequent psychiatric problems. In addition, research suggests that continued nicotine use is associated with greater rates of relapse among pathological gamblers who received behavioral therapy. Despite increased awareness of the relationship between nicotine dependence and PG, and the possible effects of nicotine dependence on gambling severity, no previous research has focused on how assessment and treatment of nicotine dependence may aid in the successful treatment of PG or smoking cessation. Preliminary research suggests that behavioral therapy using imaginal desensitization and motivational interviewing (IDMI) has shown promise in reducing the symptoms of PG. Despite the efficacy of treatments for PG and nicotine dependence, relapse is common among individuals with nicotine dependence and PG. Preclinical studies have suggested that levels of glutamate within the nucleus accumbens mediate reward-seeking behavior and may underlie relapse seen in addictions. N-acetyl cysteine, a dietary supplement, amino acid and cysteine pro-drug, appears to modulate glutamate within the nucleus accumbens and has shown benefit in reducing the reward-seeking behavior in individuals with cocaine dependence and in pathological gamblers. If successful in treating nicotine dependent pathological gamblers, N-acetyl cysteine may serve as a viable, low-cost, and easily available treatment option for nicotine dependent pathological gamblers who receive behavioral therapy. We therefore propose to examine how a dietary supplement, N-acetyl cysteine, used in combination with behavioral therapy will affect both the urge to smoke and gamble in nicotine dependent pathological gamblers and smoking and gambling behaviors. We therefore propose a randomized placebo-controlled trial of N-acetyl cysteine or placebo with 80 nicotine dependent pathological gamblers who will all receive brief standardized smoking cessation treatment (Ask, Advise, and Refer model) for nicotine cessation and 6 sessions of IDMI for PG. We hypothesize that N-acetyl cysteine plus behavioral therapy will result in greater reduction in both nicotine dependence and PG symptoms during the acute treatment phase and will enhance greater long-term abstinence. Our research will contribute to an improved understanding of the treatment of nicotine-dependent pathological gamblers as well as a greater understanding of the treatment of co-occurring addictions. If our intervention is successful, it will have the potential to set a new standard of care for a range of psychiatric disorders that co-occur with nicotine dependence. RC1 Grant Relevance Statement Nicotine dependence and pathological gambling are experienced by a broad range of individuals in multiple communities throughout the country and are associated with substantial societal costs. This study proposes to examine how a dietary supplement, N-acetyl cysteine, used in combination with brief behavioral therapy will affect both smoking and gambling behaviors. Because the study will focus treatment in non-substance abuse treatment settings and thereby offer treatment to those who may not otherwise be helped, the interventions being tested have the potential to make a substantial public health impact.